Lysosomes Flashcards
In what cells are lysosomes found?
Most except RBCs
How are macromolecules delivered to lysosomes?
By endocytosis and autophagy
What enzyme do lysosomes contain?
Hydrolases
How is lysosomal pH maintained?
Vacuolar proton pump, to keep acidic pH optima
Where do lysosomes transport the products of degradation to?
Cytosol
Material destined for degradation is delivered by what 3 pathways
Phagocytosis, autophagy and endocytosis
What is endocytosis materia
Extracellular material and plasma membrane proteins
What is autophagy material
Material from cytosol and whole cytoplasmic organelles
What are phagocytosis material
Large extracellular particulate species like microbes
What is autophagy as a process?
Constitutive process removing cytoplasmic components, enchances by cell starvation
What is macroautophagy
A type of autophagy, removes old organelles, aggregates of proteins and long-lived proteins by autophagasome. It fuses with lysosome
Lysosome involvement in apoptosis
Increased permeability of lysosomal membrane, release of lysosomal proteases called cathepsins into cytosol
Lysosomes in plasma membrane repair
Lysosomes act as a reserve membrane to repair holes, triggered by influx of Ca2+ into cell detected by lysosomal membrane protein synaptotagmin 7
What is I-cell disease?
Autosomal recessive disorder which causes fromation of intracellular inclusions
What mutation is I-cell disease from?
GNPTA which encodes enzyme N-acetylglucosimine-1-phosphotransferase
What is mucolipidosis type II otherwise called
I-cell disease
I-cell disease features
Facial and skeletal abnormalities
Severe impairment of mental abilities and movement
Heart failure in first ten years
Is there a cure for I-cell disease
No
Molecular basis for I-cell disease
Reduced intracellular levels of lysosomal hydrolases. No modified by N-acetylglucosamine-1-phosphotransferases hydrolases, so aren’t recognised by M6P receptors and are secreted
What is N-acetylglucosamine-1-phosphotransferase is involved in?
Modification of mannosylated glucans attatched to newly synthesised lysosomal hydrolases to produce M6P tag
What is Pompe disease caused by?
Autosomal recessive mutations in gene that encodes the lysosmal hydrolase lysosomal acid alpha-D-glucosidase
Clinical symptoms of Pompe disease
Progressive cardiac and skeletal myopathy
Infantile- disease occurs in first year
What does alpha-D-glucosidase do?
Lysosomal alpha-D-glucosidase cleaves glycogen into glucose that can be transported into the cytosol
Molecular basis of pompe disease
Deficiency in lysosomal ⍺-D-glucosidase
causes the abnormal accumulation of glycogen in cells and
the resultant symptoms of the disease
How is Pompe disease treated?
Enzyme replacement therapy, by IV infusions of M6P modified alpha-D-glucosidase.
What muscle is ERT most effective in (pompe)
Cardiac
What is Fabry disease?
X-linked disorder that results from mutations in alpha-galactosidase
What are the symptoms of Fabry disease?
Facial abnormalities, renal and cardiac problems
What are the symptoms of Fabry disease from?
Deposition of glycolipid Gb3 in walls of many vessels
What is the function of alpha-galactosidase
Removes terminal galactose from glycolipid globotriaosylceramide (gb3)
Molecular mechanism of Fabry disease
Lack of ⍺-galactosidase activity results in accumulationof Gb3 and in lysosomes and lipid droplets in many celltypes
Fabry disease treatments
ERT and Migalastat
How does ERT treat Fabry disease?
Administrating M6P modified form of enzyme
How does Migalastat treat Fabry’s disease?
Binds to alpha-D-glucosidase mutants in ER and stabilises them to be trafficed to lysosomes where the low pH allows drug to dissociate and enzyme to function
Infantile sialic acid storage disease is caused by… (ISASD)
Autosomal recessive mutations in sialin gene
ISASD symptoms?
facial abnormalities, intellectual disability and enlarged heart, liver and spleen. Death within 2 years
What is Salla disease caused by?
Mutations in sialin gene
In what population is Salla disease?
Finnish
Which is more severe Salla or ISASD?
ISASD
What is sialin
Lysosomal membrane transporter that transports sialic acids from lysosome to cytosol
Molecular basis of infantile sialic storage disease and Salla disease
Loss of sialin transport activity results in accumulation of sialic acids in lysosomes
